Use of serotonergic compound for a method of treatment of hot flushes in post-menopausal women

ABSTRACT

The present invention relates to a method of treatment of hot flushes with a 5-HT 2C  receptor agonist and in particular to the use of the selective 5-HT 2C  receptor agonists 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or pharmaceutically acceptable acid addition salts thereof for the manufacture of a pharmaceutical formulation adapted for the treatment of hot flushes.

[0001] The invention relates to the use of a serotonergic compound forthe treatment of hot flushes.

[0002] The most well-known complaints of the (post)-menopausal syndromeare due to changes in temperature regulation, causing sudden crises offeelings of excessive body heat (hot flushes). These symptoms are highlydisturbing for a large proportion of menopausal women, leading totherapy requests to the medical profession. Usually, replacement ofestrogens is selected as remedy. Less commonly and more recentlyexplored is the selection of non-hormonal compounds as medicine fortreating hot flushes. For example, the use of serotonergic uptakeinhibitors and serotonin (=5-hydroxy-tryptophan=5-HT) antagonists forthe treatment of hot flushes is discussed in Berendsen, Maturitas Vol36, pp 155-164, 2000. Some beneficial effects of 5-HT_(2A) antagonistsand serotonin uptake inhibitors were reported. The beneficial effect ofthe serotonin reuptake inhibitors sertraline and paroxetine weredescribed in Plouffe et al., Delaware Medical Journal 69: pp 481-482,1997, Roth and Scher, Psycho-Oncology 7, pp 129-132, 1998, and Stearnset al., Annals of Oncology 11, pp 17-22, 2000.

[0003] It has now been found that an agonist for 5-HT_(2C) receptors inan organism can be used for a method of treatment of hot flushes.

[0004] Unexpectedly, these 5-HT_(2C)-agonists produce better resultsthan SSRI's against hot flushes in view of the extent to which sideeffects are compensated for by efficacy.

[0005] Thus, the invention provides for a method of treatment of hotflushes with a 5-HT_(2C) receptor agonist. In particular, a selective5-HT_(2C) receptor agonist is preferred. A selective 5-HT_(2C) receptoragonist in the context of the description of this invention means a5-HT_(2C) receptor agonist which is more active as agonist on 5-HT_(2C)receptors than on other 5-HT receptor subtypes, such as 5-HT_(1A),5-HT_(2A) and/or 5-HT₃ receptors. The selective 5-HT_(2C) receptoragonist should preferably be such that it is at least 5 times moreactive on 5-HT_(2C) receptors than on the other serotonin receptors. The5-HT agonists described in EP 370 560 are particularly suitable for theuse of this invention. Specifically1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and itspharmaceutically acceptable acid addition salts have the most desirableproperties out of this group for the use of this invention. Morepreferred is the use of a 5-HT_(2C) agonist being at least 10 times moreactive on 5-HT_(2C) receptors relative to 5-HT_(2A) receptors. Mostpreferred is the use of the azetidines or pyrrolidine compoundsdisclosed in EP863136 for use in the treatment of hot flushes, and inparticular the compound(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or itspharmaceutically acceptable acid addition salts described in thatdisclosure.

[0006] Since the treatment of the present invention is not based onhormone replacement these treatment agents are preferably used in thosecircumstances were treatment with a hormone or a hormone receptoragonist bears higher risks. Therefore, an aspect of this invention isthat it makes a treatment available for hot flushes in patients at riskfor hormone dependent tumour growth. Such patients are the group ofpatients with ovariectomy in view of estrogen dependent tumour growth.Another aspect of the invention is that it makes a treatment availablefor hot flushes in patients with adverse feminizing responses toestrogens. In particular, male patients functionally orpharmacologically castrated for the purpose of removing endogenoushormones can be treated for hot flushes with 5-HT_(2C)-agonists. Hotflushes not only occur as complaint during menopause, but also incertain women during specific points in time of the mensual cycle, forexample before and during the days of menstruation. It is an aspect ofthis invention that hot flushes in those circumstances can be very wellnon-hormonally treated with a 5-HT_(2C) agonist.

[0007] The terms used in this description have the meaning according tocommon understanding of these terms. The accepted use of the terminologyto indicate serotonin receptor subtypes is for example used in Barnesand Sharp, Neuropharmacology 38, pp 1083-1152, 1999. A serotonergiccompound is a compound which directly or indirectly, for example asagonist or as serotonin reuptake inhibitor activates serotonin receptorsin an organism. An agonist for a receptor is a compound which producesan effect caused by conformational changes of the receptor by directbinding to the receptor. For the 5-HT_(2C) receptor the agonist mimicksat least partially the effect of serotonin. Thus, a partial agonist isexplicitly included within the scope of this invention. It is in manycircumstances beneficial to use a partial agonist rather than a fullagonist. The former might be less efficacious but may have less risk forfull-blown adverse overdose effects.

[0008] Determination of selectivity of a receptor agonist can be done bymethods well known in the art. The basic technique is with bindingexperiments in which the compound is tested for binding affinity to thesubtypes of receptors. Alternatively, selectivity can be determined within vitro expression systems in which a biochemical parameter, such ascyclic adenosine monophosphate or phosphoinositol production orinhibition is used to determine receptor activation by an agonist. Invivo methods can also be used when selective models for testing receptorstimulation are available. Some differences in the selectivity resultsobtained with these methods can occur. Usually, and under the conditionthat the test is accepted as reliable, the in vivo selectivity is thepreferred indicator for determination of selectivity of a compound overin vitro methods. Results with in vitro expression of receptor activityare in turn more preferred for determination of the selectivity thanbinding experiments. For a suitable collection of techniques todetermine the properties of a 5-HT2C agonist reference is made to Martinet al., 5-HT_(2C) receptor agonists: Pharmacological characteristics andtherapeutic potential. J. Pharmacol & Experimental Therapeutics 286:913-924, 1998

[0009] The present invention further includes the use of a5-HT_(2C)-agonist for the manufacture of a medicament for the treatmentof hot flushes.

[0010] Suitable acid addition salts include hydrochloric, fumaric,maleic, citric or succinic acid, these acids being mentioned only by wayof illustration and without implied limitation. A preferred salt is thehydrochloric acid salt.

[0011] The amount of a 5-HT_(2C) agonist, also referred to herein as theactive ingredient, which is required to achieve a therapeutic effectwill, of course, vary with the particular compound, the route ofadministration and the age and other conditions of the recipient.

[0012] A suitable daily dose for any of the two compounds chemicallynamed above will be in the range of 5 to 140 mg of the base per personper day, preferably in the range of 20 to 70 mg of the base perrecipient per day. In the case of tolerance development, treatments canbe further optimalised by increasing the dose up to 5 times in thecourse of a chronic treatment in humans. The desired dose may bepresented as one, two, three or more sub-doses administered atappropriate intervals throughout the day.

[0013] While it is possible for the active ingredient to be administeredalone, it is preferable to present it as a pharmaceutical formulation.Accordingly, the present invention further provides a pharmaceuticalformulation for use in the treatment of hot flushes comprising a5-HT_(2C)-agonist, together with a pharmaceutically acceptable carrierthereof and optionally other therapeutic agents. The carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipients thereof. Theinvention further includes a pharmaceutical formulation, as hereinbeforedescribed, in combination with packaging material suitable for thepharmaceutical formulation, said packaging material includinginstructions for the use of the pharmaceutical formulation in thetreatment of hot flush.

[0014] Formulations include those suitable for oral, rectal, nasal,topical (including transdermal, buccal and sublingual), vaginal orparenteral (including subcutaneous, intramuscular, intravenous,intradermal and epidural) administration. The formulations may beprepared by any methods well known in the art of pharmacy, for example,using methods such as those described in Gennaro et al., Remington'sPharmaceutical Sciences (18th ed., Mack Publishing company, 1990, seeespecially Part 8: Pharmaceutical Preparations and their Manufacture).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. Such accessory ingredients include those conventional inthe art, such as, fillers, binders, diluents, disintegrants, lubricants,colorants, flavoring agents and wetting agents.

[0015] Formulations suitable for oral administration may be presented asdiscrete units such as tablets or capsules each containing apredetermined amount of active ingredient; as a powder or granulates; asa solution or suspension. The active ingredient may also be presented asa bolus or paste, or may be contained within liposomes ormicroparticles.

[0016] Formulations for rectal administration may be presented as asuppository or enema.

[0017] For parenteral administration, suitable formulations includeaqueous and non-aqueous sterile injection. The formulations may bepresented in unit-dose or multi-dose containers, for example, sealedvials and ampoules, and may be stored in a freeze dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample, water prior to use.

[0018] Formulations suitable for administration by nasal inhalationinclude fine dusts or mists which may be generated by means of metereddose pressurised aerosols, nebulisers or insufflators.

[0019] Formulations may, for example, be presented in a suitablesustained release form, for example, in a device such as the Minipump™.

[0020] The compounds according to the present invention are non-toxic.

[0021] The the compounds1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine, andtheir pharmaceutically acceptable acid addition salts may be prepared byany method known in the art for the preparation of a compound of similarstructure. Typically the compound1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine can be preparedby the methods described in EP 370 560, the contents of which areincorporated herein by reference, whereas the compound(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine and itspharmaceutically acceptable acid addition salts can be prepared by themethods described in EP863136, the contents of which are incorporatedherein by reference.

[0022] The following example is for illustration and should not beconsidered to be limiting in anyway:

EXAMPLE

[0023] A test for demonstration of the effect of compounds on an acuteincrement of body heat production representative for hot flushes inhumans is based on telemetric body temperature measurements in freelymoving rats.

[0024] Method

[0025] Male rats (HSD/Cpb:WU, Harlan Sprague Dawley, Zeist, TheNetherlands), weighing 350-480 g, were used. The rats were implantedwith a Physio Tel TA11CTA-F40 Implant (Data Sciences International)under pentobarbital anaesthesia. After surgery the rats were housedindividually in a type II clear Macrolon™ cage (23×17××14 cm). The cageswere placed on receivers (RLA 1020). After a recovery and adaptationperiod of at least one week the rats were used for the experiments. Onthe experimental day, body temperature, heart rate and locomotoractivity was monitored for 30 minutes prior to injection of vehicle ortest compound. This period provides a baseline core body temperaturerelative to which the changes of body temperature after the manipulationof the rats for injection are expressed. After 30 minnutes the rats wereinjected subcutaneously with vehicle or test compound and the sameparameters were measured for at least 60 minutes. Immediately afterinjection the core body temperature rises. Compounds inhibiting thisrise in temperature reveal an inhibiting effect on acute body heatproduction. Results obtained with other parameters, such as the effecton heart rate and on locomotor activity are not presented here. 6animals were used for measurement of each dose of compound

[0026] Compounds tested are:

[0027] 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine HCl,which is indicated as Org 12962.

[0028] (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidineHCl, which is indicated as Org 37684.

[0029] Fluoxetine HCl

[0030] Data were analysed using Dataquest IV Data Acquisition System Ver2.2. Compounds were dissolved in NaCl 0.9% (m/v) in water as vehicle forsubcutaneous injection. TABLE 1 Effect of Org 37684 on temperatureincrements after manipulation of the rats relative to the bodytemperature during 30 minutes prior to the manipulation. Org 37684 Org37684 Org 37684 Org 37684 Dose: 0 mg/kg 1.0 mg/kg 2.2 mg/kg 4.6 mg/kgTime¹  5 0.50² 0.29 0.41 0.00 10 0.69 0.68 0.47 −0.03 15 0.79 0.78 0.44−0.13 20 0.80 0.58 0.40 −0.20 25 0.81 0.69 0.24 −0.14 30 0.60 0.63 0.13−0.24 35 0.40 0.49 0.04 −0.24 40 0.41 0.40 −0.05 −0.27 45 0.30 0.20−0.09 −0.34 50 0.27 0.14 −0.21 −0.40 55 0.24 0.34 −0.26 −0.43 60 0.200.14 −0.25 −0.33

[0031] TABLE 2 Effect of Org 12962; explanation as for table 1 Org 12962Org 12962 Dose: 0 mg/kg 2.0 mg/kg Time  5 0.90 0.12 10 1.06 0.10 15 1.030.06 20 0.92 −0.03 25 0.93 −0.05 30 0.83 −0.14 35 0.81 −0.19 40 0.72−0.23 45 0.66 −0.19 50 0.65 −0.24 55 0.51 −0.25 60 0.41 −0.16

[0032] TABLE 3 Effect of fluoxetine; explanation as for table 1Fluoxetine Fluoxetine Dose: 0 mg/kg 22 mg/kg Time  5 0.72 0.28 10 0.960.59 15 0.97 0.71 20 0.90 0.72 25 0.89 0.66 30 0.80 0.56 35 0.69 0.55 400.65 0.45 45 0.53 0.38 50 0.41 0.27 55 0.33 0.29 60 0.18 0.85

[0033] Interpretation of Results:

[0034] The rise in body temperature of up to slightly less than 1° C.within the period of 60 minutes after manipulation for injecting theanimals was prevented by Org 12962 or by Org 37684, but not byfluoxetine. The prevention of temperature rise was statisticallysignificant for the two 5-HT_(2C) agonists with the ANOVA/MANOVA TukeyHSD test on sample points. The results are interpreted to indicate that5-HT_(2C) agonists counteract acute increments in body temperature suchas those which occur during a hot flush.

1. A method of treatment of hot flushes, characterised in that thetreatment is with a 5-HT_(2C) receptor agonist.
 2. A use of a5-HT_(2C)-agonist for the manufacture of a medicament, characterised inthat the medicament is for the treatment of hot flushes.
 3. The methodor use according to claim 1 or 2 respectively, characterised in that the5-HT_(2C) receptor agonist is a selective 5-HT_(2C) receptor agonist. 4.The method or use according to claim 3, characterised in that theselective 5-HT_(2C) receptor agonist is selective to an extent that the5-HT_(2C) receptor agonist is at least 5 times more active on 5-HT_(2C)receptors than on other serotonin receptors.
 5. The method or useaccording to claim 3, characterised in that the selective 5-HT_(2C)receptor agonist is selective to an extent that it is at least 10 timesmore active on 5-HT_(2C) receptors than on 5-HT_(2A) receptors.
 6. Themethod or use according to claim 3, characterised in that the selective5-HT_(2C) receptor agonist is1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine or(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or apharmaceutically acceptable acid addition salt thereof.
 7. Apharmaceutical formulation adapted for the treatment of hot flushescomprising 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine or(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or apharmaceutically acceptable acid addition salt thereof, together with apharmaceutically acceptable carrier therefor.